This application requests initial support for an Exploratory Center for Translational Research on the Clinical Neurobiology of Drug Addiction (P20). The proposed UCSD Center on Interoceptive Dysregulation in Addiction (CIDIA) addresses the global question: How does the brain regulate the urge to use?, with a focus initially on What is the role of interoceptive systems in general, and insular cortex in particular, in amphetamine addiction? Interoception comprises sensing the physiological condition of the body, the conscious representation of this internal state within the context of ongoing activities, and the initiation of motivated action to regulate this state. Recent human and animal findings provide compelling evidence that interoceptive processing in the insula may mediate drug-related urges and preferences. Despite this evidence, it remains unclear how exactly the insula modulates these behaviors and what role interoceptive processing plays in different stages of addiction. To address these questions, we propose the following Specific Aims: (1) To determine the response characteristics of the interoceptive system using functional magnetic resonance imaging (fMRI) in adolescents and adults across stages of amphetamine use/addiction; (2) To delineate the causal role of interoceptive processing in mediating direct and conditioned rewarding or aversive effects in a rodent model using insula silencing via reversible inactivation of neural activity with muscimol; and (3) To integrate results of animal and human studies and provide translational predictions by (a) developing animal models of interoceptive dysfunction, (b) using predictions from animal finding to modify human neuroimaging paradigms, and (c) modifying target structures of animal silencing experiments based on human imaging studies. The goal for the Center is to impact the field of drug addiction in the following ways: (1) To develop and refine our understanding of the role of interoception for amphetamine dependence and, possibly, for addiction at large; (2) To develop translational paradigms to probe the sensitivity of the interoceptive system in animal models of drug addiction and humans in different stages of drug addiction; (3) To lay the groundwork for modulating the interoceptive system as a target for treatment; and (4) To discover risk factors or phenotypes for drug addiction involving interoceptive processing.